Crystalline forms of docetaxel and process for preparation thereof

ABSTRACT

New anhydrous crystalline form of docetaxel and process of making anhydrous docetaxel and docetaxel trihydrate are provided.

RELATED APPLICATIONS

This application claims priority from U.S. Provisional PatentApplication Ser. No. 60/853,341 which was filed on Oct. 20, 2006. Thecontent of the entire disclosure of U.S. Provisional Patent ApplicationSer. No. 60/853,341 is herein explicitly incorporated as reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel crystalline forms of docetaxeland process for the preparation thereof.

2. Description of the Related Art

Docetaxel is a compound found to exhibit anti-tumor activity. It ispresently sold under the trademark TAXOTERE®. While there are knowntechniques for synthesizing docetaxel, there is still a need forimproved chemical processes which can produce this anti-cancer compoundand in a form where the compound is chemically stable.

SUMMARY OF THE INVENTION

In accordance with the first aspect of the present invention, a novelcrystalline anhydrous docetaxel characterized by a powder x-raydiffraction with peaks at about 8.0, 12.4, and 16.8±0.2 degreestwo-theta is found.

Preferably, the novel crystalline anhydrous docetaxel is furthercharacterized by a powder x-ray diffraction pattern with peaks at about11.3, 13.8, 15.4, 20.3, and 23.3±0.2 degrees two-heta. More preferably,crystalline anhydrous docetaxel is further characterized by a powderx-ray diffraction pattern with peaks at about 4.6, 9.2, 18.1, 18.4,19.5, 20.8, 22.5, 23.7, 24.1, 28.3, and 30.6 and ±0.2 degrees two-theta.The novel crystalline anhydrous docetaxel is preferably characterized bya powder x-ray diffraction pattern as substantially depicted in FIG. 3or FIG. 4.

It is surprisingly found that the crystalline anhydrous form ofdocetaxel in accordance with the present invention is more stable thantrihydrated form (see FIG. 2). The crystalline anhydrous form ofdocetaxel in accordance with the present invention in a therapeuticallyeffective amount may be formulated with at least one pharmaceuticallyacceptable excipient to form a pharmaceutical composition. Such acomposition may be administered to a mammal, such as human, to treat aproliferative disorder.

In accordance with the second aspect of the present invention, a processof producing a crystalline anhydrous docetaxel is provided. The processcomprises (a) combining docetaxel and halohydrocarbon to form asolution; and (b) adding an antisolvent to the solution to precipitatethe crystalline. The halohydrocarbon is prefererably chlorohydrocarbon,more preferably, dichloromethane. The antisovlent may be C3-C8 linear orbranched alkanes, preferably, n-heptane.

In accordance with the third aspect of the present invention, a processof producing docetaxel trihydrate is provided. The process comprises a)combining anhydrous docetaxel, and acetonitrile; b) heating the mixtureof step a) to about 30-60° C.; c) adding water to the mixture of theheated mixture of step d); cooling the mixture of c) to about 10-30° C.to obtain a slurry; and e) filtering, washing, and drying the slurry ofstep d) to obtain docetaxel trihydrate.

The present application also provides a new process of synthesizingdocetaxel and new crystalline docetaxel trihydrate as explained indetail below.

The various features of novelty which characterize the invention arepointed out with particularity in the claims annexed to and forming apart of the disclosure. For a better understanding of the invention, itsoperating advantages, and specific objects attained by its use,reference should be had to the drawing and descriptive matter in whichthere are illustrated and described preferred embodiments of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 shows a semisynthetic process of making docetaxel.

FIG. 2 illustrates the stability of crystalline anhydrous docetaxel anddocetaxel trihydrate.

FIG. 3 shows an X-ray powder diffraction pattern of crystallineanhydrous docetaxel prepared in accordance with the process described inthe present application.

FIG. 4 lists x-ray diffraction peaks for crystalline anhydrous docetaxelprepared in accordance with the process described in the presentapplication.

FIG. 5 also shows a semisynthetic process of making docetaxel.

FIGS. 6-7 shows an X-ray powder diffraction pattern of crystallineanhydrous docetaxel prepared in accordance with the process described inthe present application.

FIG. 8 lists x-ray diffraction peaks for crystalline anhydrous docetaxelprepared in accordance with the process described in the presentapplication.

FIG. 9 shows DSC pattern of crystalline anhydrous docetaxel prepared inaccordance with the process described in the present application.

FIGS. 10-13 show IR pattern of crystalline anhydrous docetaxel preparedin accordance with the process described in the present application.

FIGS. 14-15 shows an X-ray powder diffraction pattern of crystallinedocetaxel trihydrate prepared in accordance with the process describedin the present application.

FIG. 16 lists x-ray diffraction peaks for crystalline docetaxeltrihydrate prepared in accordance with the process described in thepresent application.

FIG. 17 shows DSC pattern of crystalline docetaxel trihydate prepared inaccordance with the process described in the present application.

FIGS. 18-21 show IR pattern of crystalline docetaxel trihydrate preparedin accordance with the process described in the present application.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

As an example, the semisynthetic process used to make docetaxel isoutlined in the FIG. 1. This process comprise the synthesis of a certainoxazolidine (A-5) from (2R,3S)-3-phenylisoserine HCl as the startingmaterial. 10-deacetyl-baccatin III that has2,2,2-tri-chloroethoxy-carbonyl protecting groups in both the 7 and 10positions (SPT1141-M1) is then esterified with the oxazolidine (A-5) inthe presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine intoluene to produce an ester intermediate (SPT1141-M2). The esterintermediate is converted to docetaxel by a five-step procedure.Hydrochloric acid hydrolysis produces the β-amino ester (SPT1141-M3).T-butoxycarbonyl is attached to produce SPT1141-M4. The2,2,2-tri-chloroethoxy-carbonyl protecting groups are removed byreacting SPT1141-M4 with zinc and acetic acid to produce SPT1141-M5.Further removal of protecting groups by reaction with ozone in methanoland subsequently by reaction with o-phenylenediamine and acetic acid intetrahydrofuran produces crude docetaxel.

In the step described as Step 8a, Purification, the crude docetaxel isdissolved in ethyl acetate, filtered, concentrated under vacuum toproduce a residue, dichloromethane is added to dissolve the residue andthe solution is purified by chromatography with acetone and n-heptane asthe eluant. The purified solution is concentrated under vacuum and thedocetaxel is obtained by filtering.

In Step 8b, recrystallization—anhydrous, the purified docetaxel isdissolved in dichloromethane, n-heptane is added and the solution isseeded with docetaxel seed. The solution is cooled and the resultingslurry is filtered and the wet cake is dried to provide anhydrousdocetaxel. The resulting anhydrous docetaxel can be further converted tothe trihydrate form in Step 8c, recrystallization (trihydrate form) bymixing the anhydrous docetaxel with acetonitrile and glacial aceticacid, adding water at a temperature between 30 to 50° C., then addingmore water and seeding with docetaxel seed. The resulting slurry is thenfiltered and washed with water and the wet cake is dried under vacuum at60° C. to provide docetaxel trihydrate.

We surprisingly found that the anhydrous form of docetaxel is morestable (2168-115-16) than trihydrated form (1883-12-11, 1883-12-21,2016-109-05) in acetonitrile. See FIG. 2. Also, the anhydrous form ismore stable in acetonitrile than in acetonitrile/water (9/1). These datashowed that docetaxel is less stable in co-water solvent. Docetaxel ismore stable in non-water solvent than co-water solvent (ACN/water/aceticacid). Further more, an impurity of docetaxel, 7-epi-docetaxel, isgenerated more rapidly in co-water solvent than in non-water solvent.The growth of 7-epi-docetaxel can be suppressed by the addition ofacetic acid.

More detailed description of each step of the process shown in FIG. 2 isprovided below.

Step 1: Protection

10-Deacetyl baccatin III (approx. 14 Kg), pyridine (approx. 137 Kg), and2,2,2-trichloroethyl chloroformate (approx. 14 Kg) are charged into asuitable vessel. The resulting mixture is stirred at not more than (NMT)10° C. After the reaction is complete, the solution is quenched withwater followed by extraction with dichloromethane; the organic layer isseparated and washed with water. The organic layer is concentrated atNMT 60° C., and water is added for precipitation. The solids arecollected and washed with water. The wet cake is then suspended in ethylacetate and heptanes are added. The solids are isolated, washed, anddried under vacuum at NMT 60° C. to provide SPT1141 M1 (approx. 22 Kg).

Step 2-1: Hydrolysis

SPT2039 A4 (approx. 2.7 Kg), tetrahydrofuran (approx. 11 Kg), and about1 N lithium hydroxide solution (approx. 6.6 Kg) are charged into asuitable vessel. The mixture is stirred. After the reaction is complete,toluene and hydrochloric acid are added to adjust the mixture to pH<3.The organic layer is washed with sodium chloride solution, and magnesiumsulfate is added to remove water. The filtrate is concentrated toprovide SPT2039 A5 in toluene solution, and the mixture is used directlyin the next step.

Step 2-2: Coupling Reaction

SPT1141 M1 (approx. 3.8 Kg), toluene (approx. 11 Kg),4-dimethyiaminopyridjne (approx. 114 g), andI,³-dicyclohexylcarbondiimide (approx. 1.3 Kg) are added to the mixturefrom step 2-1. The reaction mixture is stirred. After the reaction iscomplete, the reaction mixture is quenched with hydrochloric acid. Theslurry is filtered, and the filtrate is collected and separated. Theorganic layer is washed with sodium bicarbonate solution followed bywater. The organic phase is concentrated to provide SPT11141 M2 intoluene solution, and the mixture is used directly in the next step.

Step 3: Deprotection

Tetrahydrofuran (approx. 21 Kg) is added to the above mixture. Thesolution is cooled to NMT 10° C., and a solution of hydrochloric acid inmethanol is slowly added. The mixture is stirred at below 40° C. untilthe reaction is complete. Ethyl acetate and sodium bicarbonate solutionare then added to the resulting mixture. The organic layer is collectedand washed with sodium chloride solution. After concentration, SPT1141M3 is dissolved in ethyl acetate, and the solution is used directly inthe next step.

Step 4: BOC Protection

DI-tert-butyl dicarbonate (approx. 1 Kg) is charged into a suitablevessel containing a solution of 4-dimethylaminopyridine (approx. 15 g)in SPT1141 M3 solution. After the reaction is complete, ˜the solution isquenched with diluted hydrochloric acid, and sodium chloride solution isadded. The organic layer is concentrated, and tetrahydrofuran is addedto provide SPT1141 M4 solution. The solution is used directly in thenext step.

Step 5: Deprotection

Zinc (approx. 2.7 Kg), glacial acetic acid (approx. 10.8 Kg),tetrahydrofuran, and SPT1141 M4 solution are charged into a suitablevessel. After the reaction is complete, the mixture is filtered, and thefiltrate is solvent swapped with isopropanol. Water is added to theresulting solution. The solids are filtered and washed to provide crudeSPT1141 M5 (approx. 4 Kg).

Crude SPT1141 M5 (approx. 4 Kg) and dichloromethane (approx. 54 Kg) arecharged into a suitable vessel. The solution is extracted with sodiumchloride solution. Glacial acetic acid is added to the organic layer.The mixture is then concentrated and heptanes is added forcrystallization. The solids are filtered, washed and dried to provideSPT1141 M5 (approx. 3.3 Kg).

Step 6: Ozonolysis

Ozone is added at NMT −40° C. to a suitable vessel containing a mixtureof SPT1141 M5 (approx. 5.5 Kg), methanol (approx. 88 Kg), and glacialacetic acid (approx. 55 g) while maintaining the temperature at NMT −40°C. After the reaction is complete, dimethyl sulfide are added whilemaintaining the temperature at NMT −40° C., and the mixture is warmed to20 to 30° C. The mixture is concentrated, and water is added forprecipitation. The solids are filtered, washed, and dried to provideSPT1141 M6 (approx. 4.6 Kg).

Step 7: Condensation

Glacial acetic acid (approx. 5 Kg) is charged into a suitable vesselcontaining a solution of SPT1141 M6 (approx. 4.6 Kg) and1,2-phenylenedjamine (approx. 1.8 Kg) in tetrahydrofuran (approx. 110Kg). The mixture Is then reacted under air at NMT 60° C., and1,2-phenylenediamine is added. After the reaction is complete,° thereaction mixture is concentrated and solvent swapped with methanol atNMT 60° C. The solid by-products are removed, and the filtrate is mixedwith a solution of hydrochloric acid. The solids are isolated, washed,and dried to provide crude docetaxel” (approx. 4 Kg).

Step 8a: Purification

Crude docetaxel (approx. 3 Kg) arid ethyl acetate (approx. 41 Kg) arecharged into a suitable vessel. The mixture is stirred at NMT 60° C. andis filtered through a filter bed pie-coated with Celite, activatedcarbon, and activated acidic day. The filter bed is washed with ethylacetate, and the filtrate is collected and concentrated under vacuum atNMT 60° C. until the volume of residue is approx. 9 L Dichloromethane isthen charged to the residue to provide crude docetaxel solution (forcolumn chromatography).

Step 8b: Recrystallization—Anhydrous Form

Docetaxel for crystallization (about 1 Kg) and dichioromethane arecharge into a suitable vessel. The mixture is stirred at NMT 45° C.until the solid is dissolved, and n-heptane is added forcrystallization. The slurry is filtered, washed, and dried to provideapprox. 0.8 kg of docetaxel anhydrous. The solid” is then used for thetrihydrate formation.

Step 8c: Recrystallization (Docetaxel Trihydrate)

Docetaxel anhydrous (about 0.8 Kg), acetonitriie (about 3.8 Kg) andglacial acetic acid (about 7.6 g) are charged into a suitable vessel.The mixture is heated to NMT 45° C., and purified process water (about9.6 Kg) is added for precipitation. The slurry is filtered, washed anddried under a moist environment to provide docetaxel trihydrate (about0.7 Kg).

FIG. 5 also illustrates a semisynthetic process used to make docetaxel.

The invention is not limited by the embodiments described above whichare presented as examples only but can be modified in various wayswithin the scope of protection defined by the appended patent claims.

1. Crystalline anhydrous N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol characterized by a powder x-ray diffraction pattern with peaks atabout 8.0, 12.4, and 16.8±0.2 degrees two-theta.
 2. The crystallineanhydrous N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1further characterized by a powder x-ray diffraction pattern with peaksat about 11.3, 13.8, 15.4, 20.3, and 23.3±0.2 degrees two-theta.
 3. Thecrystalline anhydrous N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol of claim 1 further characterized by a powder x-ray diffractionpattern with peaks at about 4.6, 9.2, 18.1, 18.4, 19.5, 20.8, 22.5,23.7, 24.1, 28.3, and 30.6±0.2 degrees two-theta.
 4. The crystallineanhydrous N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1characterized by a powder x-ray diffraction pattern as substantiallydepicted in FIG.
 3. 5. The crystalline anhydrousN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1characterized by a powder x-ray diffraction pattern as substantiallydepicted in FIG.
 4. 6. The crystalline anhydrousN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1 furthercharacterized by an infrared spectrum having bands at about 710, 1248,1723, 2978, and 3430 (cm⁻¹).
 7. The crystalline anhydrousN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol of claim 1 furthercharacterized by an infrared spectrum as substantially depicted in FIG.10.
 8. A process of producing crystallineN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol comprising the stepsof: coupling an oxazole intermediate of formula I:

with a baccatin III derivative of formula II:

to produce a compound of formula III:

acidifying the compound of formula III to produce a compound of formulaIV:

protecting the compound of formula IV to form a compound of formula V:

deprotecting the compound of formula V obtain a compound of formula VI:

ozonolysing the compound of formula VI to obtain a compound of formulaVII:

proceeding condensation of the compound of formula VII to obtain crudeN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol:

crystallizing the crude N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol to obtain the crystallineN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol.
 9. CrystallineN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol trihydratecharacterized by a powder x-ray diffraction pattern with peaks at about8.8, 13.9, and 17.7±0.2 degrees two-theta.
 10. The crystallineN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol trihydrate of claim9 further characterized by a powder x-ray diffraction pattern with peaksat about 4.4, 11.0, and 22.2±0.2 degrees two-theta.
 11. The crystallineN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol trihydrate of claim9 further characterized by a powder x-ray diffraction pattern assubstantially depicted in FIG.
 14. 12. The crystallineN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol trihydrate of claim9 further characterized by an infrared spectrum having bands at about710, 1268, 1737, 2981, and 3374 (cm⁻¹).
 13. The crystallineN-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol trihydrate of claim9 further characterized by an infrared spectrum pattern as substantiallydepicted in FIG.
 19. 14. A process of preparing anhydrous docetaxelcomprising the steps of: (a) combining docetaxel and halohydrocarbon tofrom a solution; and (b) adding an antisolvent to the solution toprecipitate the crystalline.
 15. The process of claim 14 wherein thehalohydrocarbon is chlorohydrocarbon.
 16. The process of claim 15wherein the chlorohydrocarbon is dichloromethane
 17. The process ofclaim 14 wherein the antisolvent is selected from the group consistingof C3-C8 linear and branched alkanes.
 18. The process claim 14 whereinthe antisolvent is n-heptane.
 19. The process of claim 14 comprising astep of maintaining the temperature of the solution of docetaxel,halohydrocarbon, and antisolvent at about 25-40° C.
 20. The process ofclaim 14 further comprising a step of cooling the solution to about0-30° C. to precipitate the crystalline.
 21. A process of producingdocetaxel trihydrate comprising: a) combining docetaxel andacetonitrile; b) heating the mixture of step (a) to about 30-60° C.; c)adding water to the mixture of the heated mixture of step b); d) coolingthe mixture of c) to about 10-30° C. to obtain a slurry; and e)filtering, washing, and drying the slurry of step (d) to obtaindocetaxel trihydrate.
 22. A composition comprising a therapeuticallyeffective amount of the crystalline anhydrous docetaxel of claim 1 andat least one pharmaceutically acceptable excipient.
 23. A method oftreating a mammal suffering from a proliferative disorder comprisingadministering to the mammal the composition of claim 21.